HU186028B - Process for preparing pyrrolo-benzoidiazepines - Google Patents

Description

The present invention relates to novel pyrrolobenzidazepines of general formula (Γ) and their acid addition salts with inorganic and organic acids of the formula:

R ¹ is hydrogen,

R ² is hydrogen or C 1-4 alkyl and

R ³ is C 1 -C 4 alkyl optionally substituted with a dialkylamino group containing 1 to 4 carbon atoms as alkyl, or

R ² and R ^{3 taken} together with the nitrogen atom to which they are attached form a pyrrolidino, pyridino or morpholino ring, or a 1-piperazinyl group optionally substituted at the 4-position,

R ⁵ is hydrogen and

^R6 széhatomos 1-4 alkyl and n is 1 or 2,

The compounds of the present invention have a protective effect on the stomach and intestines and are useful in the treatment of diseases of the body.

CO-CHH ^ NÍR ^ R ³ (I)

The present invention relates to novel pyrrolobenzidoazepines and their salts.

The compounds of the present invention are used in the pharmaceutical industry for the preparation of pharmaceutical compositions.

Anti-ulcer, secretion-inhibiting, antitussive and, in some cases, antiemetic, pyridobenzodiazepin-6-one derivatives are disclosed in U.S. Patent No. 1,795,183. U. S. Patent Publication No. 3,743,734 (corresponding to U.S. Patent No. 3,743,734), while pyridobenzodiazepin-5-ones with purely cough suppressant activity are disclosed in U.S. Patent No. 6,620,723. German Patent Publication No. (U.S. Patent No. 3,455,727). Cyclopentanobenzodiazepinones with analgesic and anxiolytic properties are disclosed in U.S. Patent Nos. 54-135,788. known from Japanese Patent Application Laid-Open. Other tricyclic compounds with sedative and antihypertensive properties are described in U.S. Patent No. 2,050,344. German Patent Publication No. (U.S. Patent No. 3,598,809, corresponding to U.S. Patent No. 3,598,809). The novel pyrrolobenzodiazepines of the present invention are not mentioned or referred to in the literature. The novel compounds have interesting and particularly advantageous pharmacological properties.

More particularly, the present invention relates to a process for the preparation of pyrrolobenzodiazepines of the formula I and their salts with inorganic and organic acids.

R ¹ is hydrogen,

R ² is hydrogen or C 1-4 alkyl and

R ³ is C 1-4 alkyl optionally substituted with a dialkylamino group containing from 1 to 4 carbon atoms per alkyl group, or

R ² and R ^{3 taken} together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino ring, a 1-piperazinyl group optionally substituted at the 4-position by a methyl or ethyl group,

R ⁴ is C 1-4 alkyl

R ⁵ is hydrogen;

R ⁶ is C 1 -C 4 alkyl and n is 1 or 2,

The process according to the invention is characterized in that:

a) a compound of Formula II wherein R 1, R ₄ , R ₅ and R ₆ are as defined above, with a compound of Formula Z-CO-C _n -L · -N (R ₂ ) R ₃ (III) wherein R ₂ , R ₃ and n are as defined above and Z is a leaving group, or

b) (VI) a compound of formula: - wherein X is halogen and R !, R _4, R _s, R _e and n are defined as ~ a H - N (R ₂₎ R ₃ (V) is an amine of formula - wherein R ₂ and R ₃ are as defined above, and optionally converting the resultant product to the acid addition salt or the resulting acid addition salt to the free base.

C 4 -C 4 alkyl is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl.

The leaving group Z is a group which, on the carbonyl group to which it is attached, forms a reactive carboxylic acid derivative. Suitable reactive carboxylic acid derivatives include acid halides, esters, anhydrides and mixed anhydrides, which are prepared, for example, from the corresponding acid (ZOH) and a chloroformate or phosphorus oxychloride.

The halogen atoms include chlorine, bromine and iodine, preferably chlorine and bromine, and in particular chlorine.

As the salt, all acid addition salts are contemplated. Particular mention may be made of the pharmaceutically acceptable salts of inorganic and organic acids which are generally useful as galenics. The pharmaceutically unacceptable salts, which may be obtained, for example, as intermediates in the bulk preparation of the compounds of the present invention, may be converted to the pharmaceutically acceptable salts in known manner.

Suitable pharmaceutically acceptable salts include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate and fumarate.

The compounds of formula (II) are reacted with the compounds of formula (III) in a known manner. Of the aforementioned Z leaving groups, we prefer those which form a mixed anhydride reactive with the carbonyl group, for example, when the appropriate acids (Z = 0H) or salts thereof are reacted with phosphorus oxychloride or ethyl chloroformate in an inert solvent. The reaction of the anhydrides with the compounds of formula II is preferably carried out in an inert, anhydrous solvent such as dimethylformamide, tetrahydrofuran or dioxane at low temperatures (e.g. -20 ° C to + 10 ° C).

The compound of formula (VI) is reacted with an amine of formula (V), preferably in the presence of a proton acceptor.

Suitable proton acceptors are, for example, alkali metal carbonates, such as sodium or potassium carbonate, or tertiary amines, such as pyridine, triethylamine or ethyldiisopropylamine.

It is also advantageous to use an excess of the compound of formula (V) as a proton acceptor to avoid side reactions. In this case, the reaction is carried out, for example, with a 2- to 5-fold excess of the compound of formula (V).

The reaction is carried out in suitable anhydrous, preferably inert, solvents such as lower alcohols (e.g. methanol, ethanol or isopropanol), open or cyclic ethers (e.g. tetrahydrofuran or especially dioxane), aromatic hydrocarbons (e.g. benzene or especially toluene) or chlorinated hydrocarbons (e.g. chloride).

The reaction temperature may range from 0 ° C to 150 ° C, with temperatures between 50 ° C and 100 ° C being preferred, especially the boiling point of the solvent used. Depending on the amine used, the reaction time may vary from a few minutes to several hours, if necessary, by adding alkali metal iodide.

When highly volatile amines are used, the reaction is preferably carried out at a lower temperature or in a closed apparatus.

Acid addition salts are prepared by dissolving the free base in a suitable solvent, such as a chlorinated hydrocarbon such as methylene chloride or chloro-21, or a lower aliphatic alcohol (ethanol or isopropanol) containing the desired acid or having the desired acid is added thereafter.

The salts may be isolated by filtration, re-precipitation, precipitation of the addition salts with a non-solvent, or distillation of the solvent.

The resulting salts can be converted into the free bases by treatment with an alkali, such as aqueous sodium bicarbonate, and the free bases converted into the acid addition salts, so that the pharmaceutically unacceptable acid addition salts can be converted into the pharmaceutically acceptable acid addition salts.

Among the compounds of formula (I) prepared according to the process of the invention, those preferred are those in which R * is hydrogen, R ² is hydrogen or C 1 -C 4 alkyl, R ³ is C 1 -C 4 alkyl, preferably substituted with dimethylamino. or R ² and R ³ together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino ring or a 1-piperazinyl group optionally substituted at the 4-position by a methyl group, R ⁴ is a methyl group, R ⁵ is hydrogen, R is methyl and n is 1 or 2. Also preferred are pharmaceutically acceptable acid addition salts of the listed compounds with inorganic or organic acids.

Particularly preferred compounds of the formula (I) according to the invention are those in which R ¹ is hydrogen, R ² is hydrogen or methyl, ethyl or propyl, R ³ is methyl, ethyl or propyl or R ² and R ³ together form a pyrrolidino, piperidino, or 4-methyl-1-piperazinyl group, R ⁴ is a methyl group, R ⁵ is a hydrogen atom, R ⁶ is a methyl group, and n is 1 and pharmaceutically acceptable acid addition salts thereof with inorganic and organic acids.

Particularly preferred preferred pyrrolobenzodiazepines which may be prepared by the process of the invention include:

4- (ethylaminoacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b [1,5] benzodiazepin-10-one,

1,3-dimethyl-4- [di (n-ropyl) aminoacetyl] -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepin-10-one, 4 - (diethylaminoacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one,

1,3-dimethyl-4- (3-pyrrolidinopropionyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one,

13-dimethyl] -4- (3-dimethylaminopropionyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one, especially

3-dimethyl-4-pyrrolidinoacetyl-1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] -benzodiazepin-10-one,

1,3-Dimethyl-4- (4-methyl-1-piperazinyl) acetyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and inorganic and pharmaceutically acceptable acid addition salts thereof with organic acids.

The compounds of formula (11) can be prepared in a variety of ways.

Compounds of formula (II) wherein R ¹ is hydrogen may also be prepared by cyclization of compounds of formula (VII)

^{R1, R4, R5} and ^R6 are as defined above and

Z'means an appropriate exit group.

A suitable leaving group Z 'is one which forms a reactive carboxylic acid derivative with the carbonyl group of the carrier. A suitable leaving group Z is, for example, an alkoxy group, an amino group or a hydroxy group. The cyclization is carried out in a known manner, depending on the quality of the leaving group. For example, when Z is an amino group, the cyclization is carried out in the presence or absence of inert solvents, preferably polar organic solvents such as lower alcohols such as ethanol, optionally in the presence of an acid (e.g. hydrogen halide) or a base (e.g. alkali metal alkanolate). at temperatures between 200 and 200 ° C, preferably at the boiling point of the solvent used. When Z 'is an alkoxy group, the compounds of formula (VII) are cyclized at a temperature of 0 to 200 ° C, preferably 20 to 160 ° C, in the presence or absence of an inert solvent and optionally in the presence of a basic or preferably acidic catalyst. The reaction time ranges from 15 minutes to 6 hours. Examples of possible solvents include alcohols such as ethanol, isopropanol or glycol, ethers such as dioxane or diphenyl ether, aromatic hydrocarbons such as toluene, xylene or o-dichlorobenzene, and dimethyl sulfoxide. Suitable catalysts include basic catalysts, such as alkali metal alkanolates such as sodium methylate or potassium tert-butylate, or preferably sodium hydride, or acidic catalysts such as organic and inorganic acids such as acetic acid, chlorine and the like. acetic acid, p-toluenesulfonic acid, o-chlorobenzoic acid, p-toluic acid, nicotinic acid, trifluoroacetic acid, fumaric acid, hydrochloric acid, benzoic acid or potassium hydrogen sulfate, and preferably phosphoric acid. Preferably, several moles of acid catalyst are used per mole of starting material.

When Z is hydroxy, the compounds of formula VII are cyclized, for example, in polar solvents, preferably in the presence of an acidic catalyst, and preferably in the presence of a condensing agent such as cyclohexylcarbodiimide, or continuously removing water from the reaction, e.g. , using a water separator. The reaction is preferably carried out at a temperature of 50 to 200 ° C, in particular 100 to 160 ° C.

Compounds of formula (VII) are prepared by reacting o-halo nitrobenzene (VIII) with pyrrole (IX)

Hal is halogen, especially fluorine or chlorine,

Y is Z is -CO- or a precursor to such a group and

^{R4, R5} and ^R6 are as defined above and the nitro group to an amino group by reduction, if desired, converting Y to an appropriate Z 'COcsoporttá.

The precursor of the Z'-CO group as Y substituent is understood to be a substituent which can be appropriately converted to the Z-CO group by known process steps (e.g., hydrolysis, alcoholysis, acid treatment, saponification, etc.). Preferred precursors of Y are the cyano group (-CN) and the carboxylate group which can be converted by hydrolysis, alcoholysis or acid treatment, to an amino group, an ester or a carboxy group.

The reaction of o-halonitrobenzenes of formula VIII with pyrroles of formula IX is carried out in a known manner, preferably by addition of a proton scavenger such as sodium hydride, potassium carbonate or a tertiary amine in a solvent (e.g. formamide, dioxane, tetrahydrofuran or N-methylpyrrolidone) and depending on the halogen content of the compound of formula (VIII) and the properties of the proton deprotecting agent used at temperatures between 0 and 150 ° C.

The pyrrole derivatives of formula (II) are known from the literature (Mu-HI.Lim, RS Klein, JF Fox, Tetrahidron Letters 21, 1013, 1980 and MuIII Lim, RS Kelin, JF Fox, J. Org. Chem., 44,3826). , 1979).

The following Examples illustrate the process of the invention in detail without limiting it. By ether is meant diethyl ether.

An ethyl ester of 3-amino-1,4,5-trimethyl-1H-pyrrole-2-carboxylic acid

A solution of 23.2 g of 2-methyl-3-oxobutyronitrile, 27.9 g (0.239 mol) of sarcosine ethyl ester and 0.2 g of p-toluenesulfonic acid in 200 ml of chloroform was heated at reflux for 2 hours until the no more water appears in the hopper. The reaction mixture was then washed with saturated aqueous sodium bicarbonate (20 mL) and water (20 mL). After drying over sodium sulfate, the mixture is concentrated in a rotary evaporator and the residual oil is taken up twice in 100-100 ml of anhydrous ethanol, and the solvent is distilled off under vacuum on a rotary evaporator. The residual oil is mixed with 300 ml of 1N sodium methylate solution was poured) and the mixture was refluxed for 2 hours. After removing the solvent in vacuo, 200 mL of ice water was added to the solid residue and the mixture was extracted several times with methylene chloride. After distilling off the solvent, a solid residue is obtained which is recrystallized from diisopropyl ether. Yield: 14.3 g, m.p. 63-64 ° C (ethanol).

2. Potassium salt of 3-amino-1,4,5-trimethyl-1H-pyrrolo-2-carboxylic acid

Ethyl 3-amino-1,4,5-trimethyl-1H-pyrrolo-2-carboxylic acid ethyl ester (36.6 g, 0.187 mol) and potassium hydroxide (11.4 g, 0.213 mol) were dissolved in methanol (200 ml) and Reflux for 4 hours. The resulting solution was evaporated to dryness and used in the next reaction without further purification.

3. Potassium salt of 1,4,5-trimethyl-3 - [(2-nitrophenyl) amino] -1H-pyrrole-2-carboxylic acid, 1-chloro-2-nitrobenzene, 38.8 g of 3- a mixture of amino-1,4,5-trimethyl-1H-pyrrole-2-carboxylic acid potassium salt (crude product of Example 2) and 36 g of ground potassium carbonate (particle size: 0.07 mm) in 120 ml of 1-methyl-2 in pyrrolidone under nitrogen at 140 ° C. After 12 hours, an additional 3.3 g

1-Chloro-2-nitrobenzene was added. For working up, the mixture is hot filtered and the filter cake is rinsed three times with 10 ml of hot 1-methyl-2-pyrrolidone (100 ° C). The combined filtrates were used without further purification.

4. 3 - [(2-Amino-phenyl) -amino] -1,4,5-trimethyl-1H-pyrrole-2-carboxylic acid

The solution obtained in Example 3, containing 61 g (0.19 mol) of the potassium salt of 1,4,5-trimethyl-3 - [(2-nitrophenyl) amino] -1H-pyrrole-2-carboxylic acid, hydrochloric acid was adjusted to pH 2 in a cylindrical hydrogenator and 0.5 g of palladium on carbon (10%) was added. When the internal temperature reaches 40 ° C, hydrogenation is started. Hydrogen is added at such a rate that the internal temperature is reduced to ca. Keep at 100 ° C. When a sudden drop in hydrogen absorption is observed, the solution is allowed to cool, filtered under nitrogen and the filter cake is washed 6 times with 5 ml of 1-methyl-2-pyrrolidone. The combined filtrates were concentrated to half volume in a rotary evaporator. The resulting solution was then worked up as in Example 5 without further purification.

5. 1,2,3-Trimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazopon-1-one

For the solution obtained in Example 4 containing 49.2 g (0.19 mol) of 3 - [(2-aminophenyl) amino] -1,4,5-trimethyl-1H-pyrrole-2-carboxylic acid, Concentrated hydrochloric acid (15 ml) was added and the mixture was kept at an internal temperature of 140 ° C for 12 hours. During heating, the water formed is continuously distilled off. During the processing of the mixture, the maximum amount of solvent is distilled off in a rotary evaporator connected to a vacuum pump. The residue is taken up in 100 ml of water and the mixture is adjusted to pH 2 with concentrated hydrochloric acid at 80 ° C. The mixture was cooled to 0 ° C with stirring. The precipitate formed is filtered off. The filtrate was extracted three times with 50 ml each of ethyl acetate. The combined filtrate was dried over sodium sulfate, concentrated and the residue was taken up in 50 ml of water. The mixture was adjusted to pH 2 with 80 ° C concentrated hydrochloric acid. The mixture was cooled to 0 ° C in an ice bath and filtered. The filter cake was washed with water and recrystallized from ethyl acetate.

6. 4- (Chloroacetyl) -1,2,3-trimethyl-1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepin-1-one g of chloroacetyl chloride Dissolve in 10 ml of toluene and add dropwise over 30 minutes at 70-80 ° C to a solution of 31 g of 1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo [3, It contains 2-bis [1,5] benzodiazepin-10-one, 6 g of anhydrous potassium carbonate, 40 ml of dioxane and 20 ml of water. The mixture was further stirred for 2 hours at 80 ° C. The mixture is concentrated to dryness, the residue is boiled three times with 25 ml of chloroform (25 ml) and the filtrate is concentrated to dryness. 3.6 g of product are obtained, m.p.

7. 1,2,3-Trimethyl - [(4-methyl-1-piperazinyl) acetyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine-1 -on (out of scope)

289 mg 4- (chloroacetyl) -1,2,3-trimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one, 200 mg N methyl piperatin and 10 ml of anhydrous dioxane

Keep at 70-80 ° C for 2.5 hours. Saturated aqueous sodium bicarbonate solution (10 ml) was added and the mixture was extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The resulting oil was taken up in a little dioxane-acetonitrile mixture and crystallized.

• 8th 3-amino-1,4,5-trimethyl-1H-pyrrole-2-carbonitrile

7.9 = (0.74 mol) of N-methylaminoacetonitrile hydrochloride was suspended in 70 ml of chloroform, and triethylamine (10.3 ml, 0.74 mol), 7.2 g (0.74 mol) was added successively. 3-cyanobutan-2-one and 0.5 g of p-toluenesulfonic acid. The mixture was refluxed for 5 hours using a water separator. After cooling, the mixture is washed twice with 10 ml of water, dried over sodium sulphate and the solvent is distilled off in vacuo. To completely remove the chloroform, the residue was taken up twice in 100-100 ml of anhydrous ethanol and the mixture was concentrated in vacuo between the two washes. The resulting oil was heated for 2 hours in 100 ml of 1N sodium methylate in ethanol (bath temperature 50 ° C), part of the ethanol was removed, the mixture was taken up in 100 ml of water and extracted several times with methylene chloride. After drying over sodium sulfate and evaporation in a rotary evaporator, the extracts give a solid which is recrystallized from diisopropyl ether.

9. 3-Amino-1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester

From 8.3 g (0.1 mol) of 3-oxobutyronitrile and 11.7 g (0.1 mol) of sarcosine ethyl ester according to the procedure of Example 1, 5.5 g of the title compound are obtained.

10. 1,5-Dimethyl-3 - [(2-nitrophenyl) amino] -1H-pyrrole-2-carboxylic acid ethyl ester

6.0 g (0.2 mol) of commercially available 80% sodium hydride (in paraffin) at 0 ° C under nitrogen (18) are added 18.2 g (0.1 mol) of 3-amino-1,5 dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester in 200 ml of anhydrous dimethylformamide. After 1 hour the gas evolution ceases. Then 28 g (0.2 mol) of 2-fluoronitrobenzene are added dropwise over 30 minutes. After 3 hours, the mixture was allowed to warm to room temperature, then poured onto 100 g of ice and extracted several times with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The resulting orange oil crystallizes completely in a short time. Yield: 22.5 g.

11. 3 - [(2-Aminophenyl) amino [1,5-dimethyl-1H-pyrrolo-2-carboxylic acid ethyl ester

To a solution of 3.0 g (0.01 mol) of 1,5-dimethyl-3 - [(2-nitrophenyl) amino] -1H-pyrrole-2-carboxylic acid ethyl ester in 50 ml of ethyl acetate was added of palladium on carbon and the mixture is hydrogenated in a cylindrical hydrogenator under gentle pressure at room temperature until the theoretical amount of hydrogen has been taken up. The catalyst is filtered off, the filtrate is concentrated in vacuo and the crystalline residue is recrystallized from a small amount of isopropanol. Yield: 2.1 g.

12.1,2-dimethyl-1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepine-10-one

2.73 g (0.01 mol) of 3 - ((2-aminophenyl) amino] -1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.25 g, 0.011 mol) are added. After cooling, the mixture was carefully neutralized with acetic acid, the solvent was distilled off in vacuo, and the yellowish residue was recrystallized from dioxane (1.9 g).

13. 4- (Chloroacetyl) -1,2-dimethyl-1,4,4,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepin-10-one

2.3 g (0.01 mol) of 1,2-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and 1.6 ml (0.02 mol) mole) of chloroacetyl chloride, after purification on neutral silica gel (methylene chloride) according to the procedure of Example 6, 1.5 g of the title compound are obtained.

14. 1,2-Dimethyl-4 - [(4-methyl-piperazin-1-yl) -acetyl] -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepine-10-π (out of scope)

303 mg (0.001 mol) of 4- (chloroacetyl) -1,2-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b [1,5] benzodiazepin-10-one and 200 mg N-Methylpiperazine (0.002 mol) was dissolved in 10 ml of anhydrous dioxane and the solution was refluxed for 2 hours. After addition of 20 ml of saturated aqueous sodium bicarbonate solution, the mixture was extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuo. The resulting oil is chromatographed on neutral silica gel (methylene chloride / n-ethanol). Yield: 280 mg.

15. 1,2-Dinethyl-4- (piperidino-ethyl) -, 4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one (out of scope)

606 mg (0.002 mol) of 4- (chloroacetyl) -1,2-dimethyl-1,4,9,9,10-tetrahydropyrrolo (3,2-b] [1,5] benzodiazepin-10-one and mg of piperidine gave 420 mg of the title compound according to the procedure of Example 14.

16.4- (Dimethylamino) -1,2-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] f 1,5] benzodiazepin-10-one (out of scope)

606 mg (0.002 mol) of 4- (chloroacetyl) -1,2-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and of the saturated alcoholic dimethylamine solution in the same manner as in Example 14 afforded 350 mg of the title compound.

17.1,2,9-Trimethyl-1,4,9,10-tetrahydropyrpro [3,2-b] f 1,5] benzodiazepin-10-one (out of scope)

0.33 g (0.011 mol) of 80% sodium hydride (in paraffin) are added 2.3 g (0.01 mol) of 1,2-dimethyl-1,4,9,10-tetralydropyrrolo [3.2 -b] [1,5] Benzodiazepine-10-tin in a cold (5 ° C) solution of dry dimethyl sulfoxide (20 mL) and tetrahydrofuran (20 mL) under nitrogen atmosphere. The mixture was stirred for 30 minutes and allowed to warm to room temperature (30 minutes). It is then cooled again to 5 ° C and a solution of methyl iodide (1.4 g, 0.01 mole) in dry tetrahydrofuran (5 ml) is added dropwise. After stirring for 2 hours at 35 ° C, 50 ml of ice water was added and the mixture was extracted several times with ethyl acetate. The combined extracts were concentrated in vacuo and the residue chromatographed on neutral silica gel (methylene chloride / methanol). Yield: 1.7 g.

18. 1,2,9-Trimethyl-4 - [(4-methylpiperazin-1-yl) acetyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5 ] benzodiazole-10-οη (out of scope)

317 mg (0.001 mol) of 4- (chloroacetyl) -1,2,9-trimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepln-10-one and N-methylpiperazine (200 mg, 0.002 mol) were obtained in the same manner as in Example 14 to give 270 mg of the title compound.

19. 3-Amino-1,4-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester

300 mg of 80% sodium hydride are added with stirring at 20 ° C to a solution of 9.1 mg of N- (2-cyano-1-propenyl) sarcosine ethyl ester in 50 ml of anhydrous dimethylformamide ( derivative is prepared by reacting methyl acrylonitrile with bromine and the product of this reaction with sarcosine ethyl ester). After warming the reaction mixture to 30 ° C, an exothermic reaction is started (the temperature rises to 45 ° C) which takes place within 30 minutes. The resulting solution of the title compound (b.p. 70 ° C, 1.3 Pa) was used without further purification.

20. 1,4-Dimethyl-3- [2-nitrophenyl) amino] -1H-pyrrole-2-carboxylic acid ethyl ester

Dimethylformamide prepared according to Example 19

A solution of 3-amino-1,4-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester was cooled to 0 ° C and mixed with 3.0 g of 80% sodium hydride and 14.1 g 2-fluoro-nitrobenzene. After removing the ice bath, the temperature rises to 40 ° C and at the same time gas evolution is observed, which disappears after 3 hours. The mixture was stirred overnight, cooled to 0 ° C and 100 g of ice and 100 ml of water were added. The precipitate formed is filtered off and washed thoroughly with cold (0 ° C) methanol. 13.5 g (87%) of the title compound are obtained, m.p. 114 ° C (from ethanol).

21. 1,4-Dimethyl-3 - [(2-nitrophenyl) amino] -1H-pyrrole-2-carboxylic acid methyl ester

The title compound, m.p. 110-113 ° C from isopropanol, prepared according to the procedure of Example 20, from 3-amino-1,4-dimethyl-1H-pyrrole-2-carboxylic acid methyl ester and 2-chloronitrobenzene.

22. 3- [3- (2-Aminophenyl) amino] -1,4-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester

A suspension of Raney nickel in ethanol was added with 80 g of ethyl 1,4-dimethyl-3 - [(2-nitrophenyl) amino] -1H-pyrrole-2-carboxylate and 30 ml of hydrazine hydrate in 2 liters of ethanol. 50 ° C) so that the temperature does not exceed 70 ° C. After 45 minutes, no nitrogen evolution was observed when Raney nickel was added. The Raney nickel was filtered hot and washed with ethanol. Concentration of the filtrate gave 58 g (82%) of the title compound, m.p. 90 ° C (from isopropanol).

23. 1,3-Dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one g 3 - [(2-aminophenyl) amino] The 1,4-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester and 30 ml of 85% phosphoric acid are thoroughly mixed in a flask and the mixture is heated to 90 ° C under a vacuum pump. After 15 minutes the mixture was allowed to cool. 50 g of ice and 100 ml of water were added and the resulting yellow precipitate was filtered off. 8.1 g (98%) of the title compound are obtained, m.p. 184 ° C (from isopropanol).

24. 4- (Chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-0-one

A solution of chloroacetyl chloride (1.47 g) in dioxane (20 ml) was added dropwise under stirring over 10 minutes at 50 ° C to 1.9 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [ 3,2-b] [1,5] benzodiazepin-10-one and 5.5 g of powdered anhydrous potassium carbonate in 50 ml of dioxane. The mixture is stirred for several hours, the precipitate is filtered off and the filtrate is evaporated to dryness. 1.75 g (69%) of the title compound are obtained, m.p. 267-269 ° C (from acetonitrile).

25. 1,3-Dimethyl-4 - [(4-methylpiperazin-1-yl) -acetyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine-10. -you

1.75 g of 4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and 1.15 g. A solution of N-methylpiperazine (g) in 50 ml of anhydrous dioxane was stirred at 50 ° C for 5 hours. After cooling, the precipitate formed is filtered off. The filtrate is concentrated, 50 ml of saturated sodium bicarbonate solution are added and the mixture is extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. 1.5 g of the title compound are obtained, m.p. 205207 DEG C. (from ethyl acetate). The dihydrochloride _mp: -ja-212 DEG C. (from water). The hemifurate had a melting point of 173 ° C (from ethanol).

26. 1,3-Dimethyl-4- (piperidinoacetyl) -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] zodiazepin-10-one

From 4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo (3,2-b] [1,5] benzodiazepin-10-one and piperidine according to the procedure of Example 25. m.p. 198 DEG C. (from isopropanol), mp 285 DEG C. (from dioxdn, dec.).

27. 1,3-Dimethyl-4- (pyrrolidinoacetyl) -1,4,19,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

From 4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and pyrrolidine from Example 25 m.p. 209-212 ° C (from isopropanol). Mp 218-220 ° C (from isopropanol).

28. 1,3-Dimethyl4- [N- (2-dimethylaminoethyl) aminoacetyl] -1,4,19,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazpine-10. -you

4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and N, N-dimethyl- ethylene diamine was prepared according to the procedure of Example 25, m.p. 176-180 ° C (from acetonitrile).

29. 1,3-Dimethyl-4- (morpholinoacetyl) -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] -benzododiazepin-10-one 4- (chloro) acetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and morpholine were prepared according to the procedure of Example 25. m.p. 208-210 ° C (from ethanol).

30. 1,3-Dimethyl-4- (1-piperazinylacetyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

Preparation of 4- (Chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and piperazine according to the procedure of Example 25. yield the title compound, m.p. 205-208 ° C (from ethanol).

31. 4- (Ethylaminoacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine-10-one

1.5 g (75%) of the title compound, m.p. 175176 ° C (from acetonitrile) - prepared by introducing ethylamine into 4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [l , 5] benzodiazepine in boiling ethanol solution.

32. 1,3-Dimethyl-4- [di- (n-propyl) -aminoacetyl] -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodjazepin-10-one.

From 4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-bj [1,5] benzodiazepin-10-one and di-n-propyl] - of the amine at 80 ° C was prepared according to the procedure of Example 25 to give the title compound, m.p. 176-177 ° C (from acetonitrile).

33. 1,3-Dimethyl-4-dimethylamino-acetyl) -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] -benzodiazepin-10-one

From 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one with excess dimethylammonium at room temperature, Example 25 The title compound was prepared by the reaction of Example 1, m.p. 219-220 ° C (from isopropanol).

34.4- (Dimethylaminoacetyl) -1,3-dimethyl-1,4,9,9,6-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepin-10-one

From 80 g of 4- (chloroacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one with diethylamine, Example 25 The title compound is prepared by m.p. 174-175 ° C (from isopropanol).

35. 4- (3-Bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

To a solution of 4.54 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine and 5.0 g of powdered anhydrous potassium carbonate in 80 ml of anhydrous dioxane was added over 10 minutes. A solution of 3.42 g of 3-bromopropionyl chloride in 20 ml of dioxane is added dropwise at 50-60 [deg.] C. and the mixture is stirred at this temperature for a further 2 hours. The solvent was evaporated in vacuo and the solid residue was stirred with 300 mL of ice water and filtered. Recrystallization from isopropanol gave 5.1 ξ of the title compound, m.p. 194-195 v (decomposition).

36. 4- (2-Bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

From 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and 2-bromopropionyl chloride according to the procedure of Example 35, m.p. 245-246 ° C (from isopropanol, decomposition).

37. 1,3-dimethyl-4- [3- (4-methyl-1-piperazinyl) propionyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepine -10 C.

1.5 g of 4- (3-bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and 0.8 µL A solution of N-methylpiperazine (50 g) in dioxane (50 ml) was heated at 80 ° C for 15 hours. The mixture was then concentrated to dryness in vacuo. Saturated aqueous sodium carbonate solution (20 mL) was added with stirring and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed in vacuo. The residue obtained is chromatographed on neutral silica gel (methylene chloride / methanol 95/5).

38. 1,3-Dimethyl-4- (3-pyrrolidinopropionyl) -1,4,9,10

-tetrahydro-pyrrolo- [3,2-b] [1,5] benzodiazepin-10-one

1,9 4- (3-bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-1-one and 0 A solution of 75 g of pyrrolidine in 50 ml of dioxane was heated at 80 ° C for 4 hours. The solvent was evaporated in vacuo and the residue taken up in a small amount of saturated sodium carbonate solution. The mixture was extracted three times with 30 ml each of ethyl acetate, and the combined extracts were dried over sodium sulfate and evaporated in vacuo. The resulting crystalline residue was recrystallized from a little acetonitrile. Yield: 1.5 g of the title compound, m.p. 185 ^% C.

39. 1,3-dimethyl-4- (3-dimethylaminopropionyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one ·

4- (3-Bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one according to the procedure of Example 38. with dimethylamine. The title compound is obtained, m.p. 175 ° C (from acetonitrile).

40.1,3-Dimethyl-4- (2-pyrrolidinopropionyl) -1,4,9- '

10-Tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

4 <2-bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and pyrrolidine, Example 3a affords the title compound, m.p. 213-215 ° C (from isopropanol).

41. 1,3-Dimethyl-4- [2- (4-methyl-1-piperazinyl) -propionyl] -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepine 10-one

4- (2-bromopropionyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one and N-methylpiperazine by the reaction of Example 38 to give the title compound, m.p. 204-205 ° C (from acetonitrile).

42. 1,3-Dimethyl-4- [4-methyl-1-piperazinyl) -acetyl] -1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepine-10- you

A mixture of 1.00 g of (4-methylpiperazin-1-yl) acetic acid and 0.20 g of 75% sodium hydride (in paraffin oil) in 16 ml of dimethylformamide until hydrogen evolution ceases (2-3 hours) 50-80 Keep at ° C. To the sodium salt formed from the acid is added 1.40 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,51] benzodiazepin-10-one and 10 min. 0.99 g of 98% purity phosphorus oxychloride was added dropwise. The reaction mixture was stirred for 4 hours at -10 ° C, for 4 hours at 0 ° C and for 20 hours at room temperature. The mixture was poured onto ice, adjusted to pH 3.5 with sodium hydroxide solution, and extracted again by extraction with methylene chloride. The organic layer was washed with water and concentrated in vacuo. 0.62 g of the title compound is obtained, m.p. 205-207 ° C (from ethyl acetate).

43. 1,3-Dimethyl-4- (pyrrolidineacetyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

Ethyl chloroformate (1.1 g) was added dropwise to a slurry of pyrrolidin-1-ylacetic acid (1.29 g) in tetrahydrofuran (20 ml). To the resulting suspension was added 2.28 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one. The mixture was stirred for 1 hour at 0 ° C and then for 1 hour at room temperature. The mixture was poured into 160 ml of 2N sodium hydroxide solution and extracted with toluene. The organic phase is evaporated to dryness. The residue is chromatographed on a silica gel column,

Using a 1: 1 mixture of dioxane and methanol. 2.1 g of the title compound are obtained, m.p. 210-212 ° C (from isopropanol).

Practical applicability

The compounds of formula (I) and their acid addition salts possess valuable properties which render them useful in practice.

These are pharmacologically active compounds which are characterized by excellent protective effects on the stomach and intestines of warm-blooded people. In particular, they inhibit the development of gastric and intestinal ulcers.

In addition, they are characterized by an advantageous therapeutic range due to their low toxicity and the total absence of significant side effects. Further, the compounds exhibit only a mild anticholinergic effect, which is a m.p. a slight inhibition of carbachol-induced saliva formation.

The excellent activity of the tricylpyrrole derivatives and their pharmaceutically acceptable acid addition salts enables their use in human and veterinary medicine for the prevention and treatment of diseases based on pathological disorders of the stomach and intestines. These compounds can be used e.g. for the treatment of acute and chronic gastric ulcer, duodenal ulcer, gastritis, gastric irritation associated with acid overproduction and drug induced gastric complaints in humans and animals.

The excellent protective effect on the stomach by the pharmacologically active tricyclic pyrroles is known as the so-called "tricyclic". It is detected using a test using Shay rats. The compounds of the present invention have been found to have a protective effect on the stomach and their therapeutic range is so superior that it clearly outperforms the known commercial product, carbenoxolone.

The compounds tested by said test are described in the following table, where the serial numbers have the following meanings:

Serial number Name of compound:

carbenoxolone

1,3-dimethyl-4 - [(4-methyl-1-piperazinyl) acetyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

1,3-dimethyl- (4- (piperidinoacetyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

1,3-Dimethyl-4- (pyrrylidoacetyl) -1,4,9,10-tetrahydro-pyrrolo [3,2-b} [1,5] benzodiazepin-10-one

4- (diethylaminoacetyl) -1,3-dimethyl-1,4,9,10-tetrahydro-pyrrolo [3,2-b] [1,5] benzodiazepin-10-one

1,3-dimethyl-4- (dimethylaminoacetyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

1,3-dimethyl-4- [di- (n-propyl) aminoacetyl] -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

4- (ethylaminoacetyl) -1,3-dimethyl-1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one 1,3-dimethyl- 4- (3-Pyrrolidinopropionyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one

1,3-Dimethyl-4- (3-dimethylaminopropyl) -1,4,9,10-tetrahydropyrrolo [3,2-b] [1,5] benzodiazepin-10-one. their effects on the inhibition of gastric ulcer induced by pylorus binding at the addition of 10 mg / kg acetylsalicylic acid in rats and the inhibition of gastric acid secretion in the following table,

Antiulcerogenic effects and toxicity of tricyclic pyrroles: __

Serial Toxicity Protective Effect TO, Inhibition of Stomach Number LDj ₀ , mg / a% Gastric LD _S0 / - acid Selection.v, ra, ED _S0 , ED _J0 % in Mice / kg in Patients with Patperoral

1 250 70.0 4.1 T 2 100 1.4 71.4 25 3 95 4.5 21.1 3 4 100 2.2 45.5 0 5 105- 6.0 17.5 20 6 6.5 10 7 110 6.5 · 16.9 10 8 140 5.5 25.5 20 9 70 6.0 11.7 '25 10 120 4.5 26.7 21

ED _S o: dose that reduces the ulcer index by 50% in the treated group compared to the control group.

LD50: is the dose at which 50% of the animals die

TO ,: therapeutic index LF = _Io / _JO ED% inhibition: The gastric acid secretion inhibition% in 4 hours after administration of the substance antiulcerogén ED _S0 unto in suitable amounts.

We must particularly emphasize the fact that it is

An ED _S0 value for Compound 1 can still be determined, but the dose / effect curve flattens very suddenly after this value, so that no significant increase in antiulcerogenic effect can be observed even at 300 mg / kg. In contrast, the activity of the compounds of the invention is highly dose-dependent, with up to 99% (30 mg / kg) inhibition achieved.

The study of the antagonistic effect is the so-called This was done using a method based on using rat Shay. Female rats weighing 180-200 g (4 animals / cage, high grid), fasted for 24 hours, were exposed to ulcer-producing conditions by ligation of the pylorus (with diethyl ether anesthetic) and 100 mg) orally with 10 mg / kg acetylsalicylic acid. Test substances were orally administered 1 hour prior to binding at 10 mg / kg. The wound was closed with Michel clips. After 4 hours, the animals were killed by ether narcosis by displacement of the atlas and the stomach was removed. The stomach was opened longitudinally and fixed on a cork plug (cylindrical) after the volume of the selected stomach acid was determined. The number and size (diameter) of the ulcers formed were then determined using a seromicroscope at 10x magnification. As a unique ulcer index, we take the product of severity (according to the following scale) and the number of ulcers.

Point scale:

ulcer is absent θ ulcer meter 0.1 -1.4 mm 1

1.5 - 2.4 mm 2

2.5 - 3.4 mm 3

3.5 - 4.4mm 4

4.5 to 5.4 mm 5

Above 5.5 mm 6

The antiulcerogenic effect is measured by a reduction in the mean ulcer index of each treatment group relative to the control group (100%). The ED 50 value is the dose that reduces the average ulcer index by 50%.

Determination of toxicity

Toxicity was determined in female NMRI mice (body weight: 23-30 g). The animals (5 animals / dose) were fed ad libitum with food and water. Different doses of the substances were administered intravenously (injection time: 1 minute). The observation period is 7 days. LD _S0 (the dose at which 50% of the animals die) is determined by linear regression.

In human or veterinary medicine, tricyclic pyrrole derivatives are introduced as pharmaceutical formulations.

The pharmaceutical compositions are prepared by known methods. As the pharmaceutical composition, the pharmacologically active compound is used as such or preferably in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions.

186 028

For oral therapy in human therapy, the daily dose will generally be in the range of approx. 0.3 approx. It ranges from 150, preferably from 1.5 to 75 and especially from 3 to 15 mg / kg body weight. 5

Claims (2)

Patent claims A process for the preparation of pyrrolobenzodiazepes of the formula I and their acid addition salts with inorganic and organic acids of the formula: R ¹ is hydrogen, R ² is hydrogen or C 1-4 alkyl and R ³ represents C 1-4 alkyl optionally substituted by a dialkylamino group He- ⁰ lyettesített containing 1-4 carbon atoms aíkilcsoportonként or R ² and R ^{3 taken} together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholine ring, or a 1-piperazinyl group optionally substituted at the 4-position with a methyl or ethyl group, R ⁴ is C 1-4 alkyl, R ⁵ is hydrogen and R ^e is C 1 -C 4 alkyl and n is 1 or 2, characterized in that a) a compound of formula II wherein R 1, R ₄ , R ₅ and R _e are as defined above, a compound of formula Z-CO-C _n H ₂ -N (R ₂ ) R ₃ ) (III) with a compound of the formula wherein R ₂ , R ₃ and n are as defined above and Z is a leaving group; or b) a compound of Formula VI: wherein X is halogen and R 1, R ₄ , R 5, R 1 and n are as defined above, with an amine of formula H-N (R ₂ ) R ₃ (V) wherein R ₂ and R ₃ are as defined above and optionally the product of process a) or b) is added to the acid addition salt. or converting the resulting acid addition salt to the free base. (Priority: March 26, 1981) 2. Process according to claim 1, characterized in that the starting materials of the general formulas (II) and (III) or (V) and (VI) R ¹ is hydrogen, R ² is C 1 -C 4 alkyl, R ³ is C 1-4 alkyl optionally substituted by a dialkylamino group containing from 1 to 4 carbon atoms per alkyl group, or R ² and R ^{3 taken} together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino ring, or a 1-piperazinyl group optionally substituted at the 4-position, R ⁴ is methyl, R ⁵ is hydrogen, R ⁶ is methyl and n is 1 or 2; Z represents a leaving group and X represents a chlorine or bromine atom. (Priority: 1981. VIII. 26.)